JP2008197053A - Flow-channel formation chip for biological sample, and manufacturing method for the flow-channel formation chip for biological sample - Google Patents

Flow-channel formation chip for biological sample, and manufacturing method for the flow-channel formation chip for biological sample Download PDF

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JP2008197053A
JP2008197053A JP2007034987A JP2007034987A JP2008197053A JP 2008197053 A JP2008197053 A JP 2008197053A JP 2007034987 A JP2007034987 A JP 2007034987A JP 2007034987 A JP2007034987 A JP 2007034987A JP 2008197053 A JP2008197053 A JP 2008197053A
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flow path
biological sample
phosphor
flow
optical fiber
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Hisaaki Oguchi
寿明 小口
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NSK Ltd
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<P>PROBLEM TO BE SOLVED: To provide a flow-channel formation chip for a biological sample capable of accurately measuring the temperature, without having to correct radiation efficiency in response to a measuring object as required in a radiation thermometer, and without being affected by high frequency and high voltage as in a thermocouple, a platinum resistance thermometer bulb and the like, and to provide a manufacturing method for the flow-channel formation chip. <P>SOLUTION: This flow-channel formation chip is provided with a fluorescence-type temperature measuring member, having a plate-like substrate provided on a surface with a flow channel for making the biological sample flow; a reflecting film allowing contact with the biological sample in the flow channel; a phosphor attached to the reflecting film; a light source for irradiating the phosphor with an excitation light; a temperature-measuring part for measuring the temperature of the biological sample, based on an attenuation characteristics of a light emission intensity in the phosphor due to the excitation light, and an optical fiber for connecting the phosphor to the light source; and the phosphor is interposed between an end part of the optical fiber and the reflecting film. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は、生体試料の温度を測定するための手段を備える生体試料用の流路形成チップ、その流路形成チップの製造方法に関する。   The present invention relates to a flow channel forming chip for a biological sample including means for measuring the temperature of the biological sample, and a method for manufacturing the flow channel forming chip.

近年、ＤＮＡ、ＲＮＡ、細胞といった種々の生体試料等に対する生化学的な分析操作は、流路形成チップを利用している。この流路形成チップはガラス、ポリマーからなる薄板状基板からなり、半導体集積回路に用いられる微細加工技術等を利用して、その基板表面に微細な流路が形成されている。そして、生体試料等の測定対象物を測定、分離等するために、流路形成チップの流路の両端に高電圧を印加することで形成された電気浸透流が利用される（電気泳動法）（例えば、特許文献１参照。）。   In recent years, biochemical analysis operations for various biological samples such as DNA, RNA, cells, and the like have used flow path forming chips. This flow path forming chip is made of a thin plate substrate made of glass or polymer, and a fine flow path is formed on the surface of the substrate by utilizing a fine processing technique used in a semiconductor integrated circuit. Then, in order to measure and separate a measurement object such as a biological sample, an electroosmotic flow formed by applying a high voltage to both ends of the flow path of the flow path forming chip is used (electrophoresis method). (For example, refer to Patent Document 1).

生化学的な分析操作を高い精度で行うためには、生体試料の温度管理を高精度で行うことが重要である。従来より、流路形成チップに用いられる温度測定手段としては、被測定物が放射する赤外線を検出する放射温度計（例えば、特許文献２参照。）や、2種類の異なる金属で閉回路を形成し、2箇所の接合点で温度差により生じる起電力(電圧)に基づき温度を測定する熱電対や、温度の変化を抵抗値若しくは定電流信号として取り出し、信号変換器により温度に換算して利用する白金測温抵抗体などが知られている（例えば、特許文献３参照）。
特開２００５−２８３１７３ 特開２００３−０４９８３２ 特開平１０−３０７０６５ In order to perform biochemical analysis operations with high accuracy, it is important to perform temperature management of biological samples with high accuracy. Conventionally, as a temperature measuring means used for a flow path forming chip, a radiation thermometer (for example, refer to Patent Document 2) that detects infrared rays emitted from an object to be measured, or a closed circuit is formed using two different metals. The thermocouple that measures the temperature based on the electromotive force (voltage) generated by the temperature difference at the two junctions, and the change in temperature is extracted as a resistance value or constant current signal, and converted to temperature by a signal converter and used A platinum resistance temperature detector is known (for example, see Patent Document 3).
JP 2005-283173 A JP 2003-049832 A JP 10-307065

ここで、生体試料の測定、分離等を高精度で行うためには、生体試料、もしくはその周囲の環境の温度を正確に測定し制御することが必要である。
ところが、測定対象物の材質や表面状態により赤外線の放射量に差異が生じる放射温度計を流路形成チップに適用した場合には、測定対象物の放射率を考慮して（すなわち放射量を補正して）、測定対象物の温度を算出する必要があり、その放射率を得るには手間がかかる。さらに、測定対象物以外から放射される赤外線をも区別されることなく放射量として測定してしまい、正確な温度測定が困難である。また、赤外線の波長サイズによっては、非常に高い温度分解能が要求され、正確な温度測定をするにはコストが嵩む恐れがある。 Here, in order to measure and separate a biological sample with high accuracy, it is necessary to accurately measure and control the temperature of the biological sample or the surrounding environment.
However, when a radiation thermometer that produces a difference in the amount of infrared radiation depending on the material and surface condition of the measurement object is applied to the flow path forming chip, the emissivity of the measurement object is taken into consideration (that is, the radiation amount is corrected). Therefore, it is necessary to calculate the temperature of the measurement object, and it takes time to obtain the emissivity. Furthermore, infrared rays emitted from other than the measurement object are also measured as radiation amounts without being distinguished, and accurate temperature measurement is difficult. In addition, depending on the wavelength size of infrared rays, a very high temperature resolution is required, and there is a risk that cost may be increased for accurate temperature measurement.

また、熱電対や白金測温抵抗体などの温度測定手段を、流路形成チップに適用した場合には、電気浸透流を形成するために高周波の高電圧を印加する場合があるので、電気的な信号に基づいて温度を測定する温度測定手段では、信号ノイズが生じる場合があり、高い精度で温度を測定することが難しい。   In addition, when a temperature measuring means such as a thermocouple or a platinum resistance thermometer is applied to the flow path forming chip, a high frequency high voltage may be applied to form an electroosmotic flow. In a temperature measuring means for measuring temperature based on a simple signal, signal noise may occur, and it is difficult to measure temperature with high accuracy.

そこで、本発明は、放射温度計のように測定対象物に応じて放射効率を補正することがなく、また、熱電対や白金測温抵抗体等のように高周波及び高電圧の影響を受けることがなく、高精度で温度の測定が可能な生体試料用の流路形成チップ、及び当該流路形成チップの製造方法を提供することを目的とする。   Therefore, the present invention does not correct the radiation efficiency according to the object to be measured unlike a radiation thermometer, and is affected by high frequency and high voltage like a thermocouple or a platinum resistance thermometer. It is an object of the present invention to provide a flow channel forming chip for a biological sample capable of measuring temperature with high accuracy and a method for manufacturing the flow channel forming chip.

発明者等が鋭意検討した結果、蛍光体式測温手段は、高周波で高電圧の環境下で使用しても、信号ノイズの影響を受けることが相対的に小さいので、安定して高精度で温度測定ができるということを知得した。なお、蛍光式温度測定手段は、生体試料に接触した蛍光体を、パルス状の励起光を照射することにより発光させ、蛍光体の発光強度の時間に関する減衰曲線が温度に応じて変化するという物理的原理を応用したものである。   As a result of intensive studies by the inventors, the phosphor temperature measuring means is relatively less affected by signal noise even when used in a high-frequency and high-voltage environment. I knew that I could measure. The fluorescent temperature measuring means causes the phosphor that has contacted the biological sample to emit light by irradiating it with pulsed excitation light, and the decay curve of the emission intensity of the phosphor changes with time. It is an application of the general principle.

上記課題を解決するための本発明の流路形成チップの第１の態様は、生体試料を流動させるための流路が表面に設けられた板状の基板と、前記流路内の前記生体試料に接触可能な反射膜と、前記反射膜に装着された蛍光体と、前記蛍光体に励起光を照射する光源と、前記励起光による前記蛍光体の発光強度の減衰特性から前記生体試料の温度を測定する測温部と、前記蛍光体に前記光源及び前記測温部を連結する光ファイバと、を有する蛍光式温度測定部材と、を備え、前記蛍光体は、前記光ファイバの端部と前記反射膜との間に介在している。   The first aspect of the flow path forming chip of the present invention for solving the above problems is a plate-like substrate provided with a flow path for flowing a biological sample on the surface, and the biological sample in the flow path. A reflective film that can be contacted with the phosphor, a phosphor mounted on the reflective film, a light source that irradiates the phosphor with excitation light, and a temperature of the biological sample from the decay characteristics of the emission intensity of the phosphor by the excitation light A fluorescent temperature measuring member having a temperature measuring unit for measuring the light source, and an optical fiber connecting the light source and the temperature measuring unit to the phosphor, and the phosphor has an end of the optical fiber; It is interposed between the reflection films.

また、本発明の流路形成チップの第２の態様によれば、反射膜は、熱伝導体である。
さらに、本発明の流路形成チップの第３の態様によれば、前記反射膜は、反射率が相対的に高い、金属膜もしくは誘電体多層膜である。 Moreover, according to the 2nd aspect of the flow-path formation chip | tip of this invention, a reflecting film is a heat conductor.
Furthermore, according to the third aspect of the flow path forming chip of the present invention, the reflective film is a metal film or a dielectric multilayer film having a relatively high reflectance.

本発明の流路形成チップの第４の態様によれば、前記蛍光式温度測定部材が、複数配置されている。
本発明の流路形成チップの第５の態様によれば、前記光ファイバの一端部には、前記反射膜および前記蛍光体を覆うようにキャップが装着されている。 According to the fourth aspect of the flow path forming chip of the present invention, a plurality of the fluorescent temperature measuring members are arranged.
According to the fifth aspect of the flow path forming chip of the present invention, a cap is attached to one end of the optical fiber so as to cover the reflective film and the phosphor.

さらに、本発明の流路形成チップの第６の態様によれば、前記流路の一端部と他端部それぞれに、前記生体試料を流動させるための電極が形成されている。
本発明の流路形成チップの第７の態様によれば、前記流路内で移動可能に配された検出媒体を備え、前記流路の途中には、前記検出媒体の移動を拘束する検出部が設けられている。 Furthermore, according to the 6th aspect of the flow-path formation chip | tip of this invention, the electrode for making the said biological sample flow is formed in each one end part and other end part of the said flow path.
According to the seventh aspect of the flow path forming chip of the present invention, the detection unit includes a detection medium movably arranged in the flow path, and restrains the movement of the detection medium in the middle of the flow path. Is provided.

上記課題を解決するための本発明の生体試料用の流路形成チップの製造方法の第１の態様は、板状の基材と、蛍光式温度測定部材に連結可能な光ファイバと、を用意し、前記基板の表面の所定位置に前記光ファイバを固定し、前記基板の前記光ファイバが固定された面に光感応性樹脂を積層し、所定の流路パターンを有するマスクを介して前記光感応性樹脂に紫外線を照射し、前記光感応性樹脂を現像し、前記所定の流路パターンを有する流路を形成し、前記光ファイバの一端部は、前記流路を移動する前記生体試料に接するように前記流路に面するように配置される。   In order to solve the above-mentioned problems, a first aspect of a method for manufacturing a flow channel forming chip for a biological sample according to the present invention provides a plate-like substrate and an optical fiber that can be connected to a fluorescent temperature measuring member. The optical fiber is fixed at a predetermined position on the surface of the substrate, a photosensitive resin is laminated on a surface of the substrate on which the optical fiber is fixed, and the light is passed through a mask having a predetermined flow path pattern. The photosensitive resin is irradiated with ultraviolet rays, the photosensitive resin is developed, a flow path having the predetermined flow path pattern is formed, and one end of the optical fiber is attached to the biological sample moving through the flow path. It arrange | positions so that the said flow path may be touched.

さらに、本発明の生体試料用の流路形成チップの製造方法の第２の態様によれば、前記流路の一端部と他端部それぞれ前記光感応性樹脂はポジ型又はネガ型である。
また、本発明の生体試料用の流路形成チップの製造方法の第３の態様によれば、前記基板に固定される前記光ファイバは複数である。 Furthermore, according to the 2nd aspect of the manufacturing method of the flow-path formation chip | tip for biological samples of this invention, the said photosensitive resin is a positive type or a negative type respectively at the one end part and other end part of the said flow path.
Moreover, according to the 3rd aspect of the manufacturing method of the flow-path formation chip | tip for biological samples of this invention, the said optical fiber fixed to the said board | substrate is plurality.

本発明によれば、蛍光式温度測定手段を用い、生体試料に接触する蛍光体にパルス上の励起光を照射することによる蛍光物質の光強度の減衰曲線を測定することにより、生体試料を測定するので、放射温度計と異なり放射効率を補正する必要もない。また、蛍光式温度測定手段は、高周波で高電圧の影響が非常に小さい。結果として、生体試料の温度を高精度で測定できる生体試料用の流路形成チップ、及び当該流路形成チップの製造方法を提供することができる。   According to the present invention, a biological sample is measured by measuring the decay curve of the light intensity of the fluorescent substance by irradiating the fluorescent material in contact with the biological sample with excitation light on the pulse using the fluorescent temperature measuring means. Therefore, unlike the radiation thermometer, there is no need to correct the radiation efficiency. In addition, the fluorescent temperature measuring means has a very high frequency and is hardly affected by a high voltage. As a result, it is possible to provide a flow channel forming chip for a biological sample that can measure the temperature of the biological sample with high accuracy, and a method for manufacturing the flow channel forming chip.

以下、本発明の生体試料用の流路形成チップを適用した実施形態について図面を参照しつつ説明する。各図面中、同一要素は同一符号で示してある。   Hereinafter, an embodiment to which a flow channel forming chip for a biological sample of the present invention is applied will be described with reference to the drawings. In the drawings, the same elements are denoted by the same reference numerals.

（実施形態１）
本発明の実施形態１である流路形成チップについて、図１、２を参照しつつ説明する。図１(ａ)は、流路形成チップの斜視図である。図１（ｂ）は図１（ａ）の流路形成チップの平面図である。図２は、蛍光性温度測定手段の構成図である。図２は、蛍光式温度測定部材の構成を模式的に示す図である。尚、図１（ａ）、（ｂ）は、構成を理解を容易にするため光ファイバが露出した状態で示している。同様に、図１（ｂ）から後述のＣＣＤカメラ２３を割愛した。 (Embodiment 1)
The flow path forming chip according to the first embodiment of the present invention will be described with reference to FIGS. FIG. 1A is a perspective view of a flow path forming chip. FIG.1 (b) is a top view of the flow-path formation chip | tip of Fig.1 (a). FIG. 2 is a block diagram of the fluorescent temperature measuring means. FIG. 2 is a diagram schematically showing the configuration of the fluorescent temperature measuring member. 1A and 1B show the optical fiber exposed for easy understanding of the configuration. Similarly, a later-described CCD camera 23 is omitted from FIG.

本実施形態の生体試料を検査するための流路形成チップ１は、ＤＮＡや細胞等の生体試料２５を流動させるための流路５が表面に設けられた板状の基板３と、蛍光式温度測定部材１３と、を備える。なお、基板３には、流路５と交差する方向に延びる生体試料を導入するための生体試料導入流路３９を設けているが、本発明の必須構成要件ではない。   A flow path forming chip 1 for inspecting a biological sample of this embodiment includes a plate-like substrate 3 provided with a flow path 5 for flowing a biological sample 25 such as DNA or cells on the surface, and a fluorescent temperature. A measuring member 13. The substrate 3 is provided with a biological sample introduction flow path 39 for introducing a biological sample extending in a direction intersecting the flow path 5, but this is not an essential component of the present invention.

蛍光式温度測定部材１３は、流路５内の生体試料２５の温度を伝達可能な熱伝導体である反射膜３１と、反射膜３１に装着された蛍光体２７と、蛍光体２７に励起光を照射する光源９と、励起光による蛍光体２７の発光強度の減衰時間から生体試料の温度を測定する測温部１９と、反射膜３１と光源９及び測温部１９とを連結する光ファイバ７と、を有する。さらに、蛍光体２７は、光ファイバ７の一端部７ｂと反射膜３１との間に介在している。すなわち、蛍光体２７は、光ファイバ７の一端部７ｂと反射膜３１とに挟まれた構成である。なお、光源９としては、青色ＬＥＤ等の公知の発光手段を用いるこができる。   The fluorescent temperature measuring member 13 includes a reflection film 31 that is a heat conductor capable of transmitting the temperature of the biological sample 25 in the flow path 5, a phosphor 27 attached to the reflection film 31, and excitation light on the phosphor 27. , A temperature measuring unit 19 for measuring the temperature of the biological sample from the decay time of the emission intensity of the phosphor 27 by the excitation light, and an optical fiber connecting the reflective film 31, the light source 9, and the temperature measuring unit 19. 7. Further, the phosphor 27 is interposed between the one end 7 b of the optical fiber 7 and the reflective film 31. That is, the phosphor 27 is sandwiched between the one end 7 b of the optical fiber 7 and the reflective film 31. As the light source 9, a known light emitting means such as a blue LED can be used.

さらに、光ファイバ７の一端部７ｂには、反射膜３１および蛍光体２７を覆うように、断面が略Ｕ字状のキャップ３３が装着されている。キャップ３３は、流路５の一方の壁面５ａの一部を構成している。従って、生体試料２５の温度は、キャップ３３、反射膜３１を介して蛍光体２７に伝達される。   Further, a cap 33 having a substantially U-shaped cross section is attached to one end portion 7 b of the optical fiber 7 so as to cover the reflective film 31 and the phosphor 27. The cap 33 constitutes a part of one wall surface 5 a of the flow path 5. Therefore, the temperature of the biological sample 25 is transmitted to the phosphor 27 through the cap 33 and the reflective film 31.

なお、反射膜３１及び蛍光体２７が生体試料に直接接すると、生体試料の種類によっては、反射膜、蛍光体、生体試料の変質等を起こす場合がある。キャップ３３は、このような好ましくない影響を防止するために使用している部材であり、本発明の必須構成要素ではない。また、キャップ３３は、生体試料２５に直接接する部材であるので、生体試料２５の温度変化を忠実に反映するような熱伝達率の高い部材を使用することが望ましい。   When the reflective film 31 and the phosphor 27 are in direct contact with the biological sample, the reflective film, the phosphor, the biological sample may be altered depending on the type of the biological sample. The cap 33 is a member used to prevent such an undesirable influence, and is not an essential component of the present invention. Further, since the cap 33 is a member that is in direct contact with the biological sample 25, it is desirable to use a member having a high heat transfer coefficient that faithfully reflects the temperature change of the biological sample 25.

また、光ファイバ７の一端部７ｂの垂直方向上方には、基板３を向いたＣＣＤカメラである撮像装置２３が配置され、流路形成チップ１を使用する者が流路５を移動する生体試料２５を観察できる構成となっている。   In addition, an imaging device 23 that is a CCD camera facing the substrate 3 is disposed above the one end 7b of the optical fiber 7 so that a person using the flow path forming chip 1 moves through the flow path 5 25 can be observed.

さらに、図２を参照して蛍光式温度測定部材１３について説明する。本実施形態の蛍光式温度測定部材１３は、上記したように、反射膜３１、蛍光体２７、光源９、測温部１９、光ファイバ７に加え、ビームスプリッタ２９と、フィルタ３５とを備える。ビームスプリッタ２９は、光源９からの励起光を９０度反射させて光ファイバ７に導波し、また、光ファイバ７を出射した蛍光体２７からの光線５３を透過させる部材である。また、フィルタ３５は、蛍光体２７からの光線５３のうち、所定波長の光を透過させる部材である。   Further, the fluorescent temperature measuring member 13 will be described with reference to FIG. As described above, the fluorescent temperature measuring member 13 of the present embodiment includes the beam splitter 29 and the filter 35 in addition to the reflective film 31, the phosphor 27, the light source 9, the temperature measuring unit 19, and the optical fiber 7. The beam splitter 29 is a member that reflects the excitation light from the light source 9 by 90 degrees and guides it to the optical fiber 7 and transmits the light beam 53 from the phosphor 27 that has exited the optical fiber 7. The filter 35 is a member that transmits light of a predetermined wavelength among the light rays 53 from the phosphor 27.

また、測温部１９は、光検出部１５と温度検出部１７とを有する。光検出部１５は、フィルタ３５を透過した光を電荷に変換する光電変換部材であり、温度検出部１７は、光検出部１５で得られた電荷に基づいて算定された蛍光体の発光強度の減衰特性と、予め格納されている蛍光輝度の減衰特性とを比較して、温度を測定する部材である。   The temperature measuring unit 19 includes a light detection unit 15 and a temperature detection unit 17. The light detection unit 15 is a photoelectric conversion member that converts the light transmitted through the filter 35 into electric charge, and the temperature detection unit 17 has the emission intensity of the phosphor calculated based on the electric charge obtained by the light detection unit 15. It is a member that measures the temperature by comparing the attenuation characteristic with the attenuation characteristic of the fluorescence brightness stored in advance.

上記構成の蛍光式温度測定部材１３において、光源９から照射される励起光５１は、図２中の上下方向上方に進行する。さらに、ビームスプリッタ２９により励起光５１を９０度反射させ光ファイバ７内の端部７ａへ導入する。光ファイバ７内を進行する励起光５１は、光ファイバ蛍光体２７に到達し蛍光体２７が発光する。蛍光体２７から放出される放出光５３は、直接光ファイバ７の端部７ａ側に進行する光線と、反射膜３１で反射し光ファイバ７内を端部７ａ側に進行する光線から構成される。放出光５３は、光ファイバ７の端部７ａから出射し、ビームスピリッタ２９、フィルタ３５を透過し測温部１９内に入射する。上述のように測温部１９において蛍光体の発光強度の減衰に基づき生体試料の温度が計測される。   In the fluorescent temperature measuring member 13 having the above configuration, the excitation light 51 emitted from the light source 9 travels upward in the vertical direction in FIG. Further, the excitation light 51 is reflected by 90 degrees by the beam splitter 29 and introduced into the end portion 7 a in the optical fiber 7. The excitation light 51 traveling in the optical fiber 7 reaches the optical fiber phosphor 27 and the phosphor 27 emits light. The emitted light 53 emitted from the phosphor 27 is composed of a light beam that travels directly to the end portion 7a side of the optical fiber 7 and a light beam that is reflected by the reflection film 31 and travels inside the optical fiber 7 toward the end portion 7a side. . The emitted light 53 is emitted from the end 7 a of the optical fiber 7, passes through the beam spiriter 29 and the filter 35, and enters the temperature measuring unit 19. As described above, the temperature measuring unit 19 measures the temperature of the biological sample based on the decay of the emission intensity of the phosphor.

次に、光ファイバに蛍光体及び反射膜を形成する工程について図３を参照して説明する。図３（ａ）〜（ｃ）は、測温部１９に連結される測温光ファイバ７を作製する工程を示す横断面図である。図３（ａ）に示されるように、最初に、光ファイバ７の端面７ｂに蛍光体２７を作製する。蛍光体の作製は、例えば、蛍光体（微粒子）を樹脂に混入した材料を成膜したり、蛍光フィルムを貼り付けることにより行われる。次に、蛍光体２７の端面に反射率の高い、金属膜（Ａｕ、Ｐｔ、Ａｌ、等）または誘電体多層膜（ＴｉＯ２（ｎ＝２．４）／ＳｉＯ２（ｎ＝１．４６）による多層膜等）などの反射膜３１を真空蒸着等により形成する（図３（ｂ）参照）。最後に、光ファイバ７の端面７ｂ、蛍光体２７、反射膜３１を覆うようにキャップ３３を装着する。
さらに、流路形成チップの作製方法について図４を参照しつつ説明する。図４（ａ）〜（ｄ）は、流路形成チップ１を作製する工程を示す横断面図である。 Next, the process of forming the phosphor and the reflective film on the optical fiber will be described with reference to FIG. FIGS. 3A to 3C are cross-sectional views showing a process of manufacturing the temperature measuring optical fiber 7 connected to the temperature measuring unit 19. As shown in FIG. 3A, first, the phosphor 27 is produced on the end face 7 b of the optical fiber 7. The phosphor is manufactured by, for example, forming a film of a material in which a phosphor (fine particles) is mixed in a resin, or attaching a phosphor film. Next, a highly reflective metal film (Au, Pt, Al, etc.) or dielectric multilayer film (TiO 2 (n = 2.4) / SiO 2 (n = 1.46) is formed on the end face of the phosphor 27. A reflective film 31 such as a multilayer film is formed by vacuum deposition or the like (see FIG. 3B). Finally, a cap 33 is attached so as to cover the end face 7 b of the optical fiber 7, the phosphor 27, and the reflective film 31.
Further, a manufacturing method of the flow path forming chip will be described with reference to FIG. 4A to 4D are cross-sectional views showing a process of manufacturing the flow path forming chip 1.

まず、板状のガラス基材３ａを用意する。次に、図４（ａ）に示されるようにガラス基材３ａの上面の所定位置に光ファイバ７（図３参照。）を接着剤等により固定する。さらに、ガラス基材３ａの上面に、光ファイバ７を覆い、かつ、流路の流路壁を構成する流路構成部材３ｂを所定厚さで積層する。流路構成部材３ｂの材料としては、PMMA（ポリメチルメタクリレート：poly(methylmethacrylate)）、PDMS（ポリディメチルシロキサン：poly(dimethylsiloxane)）、ポリカーボネート、レジスト類などを主とした感光剤を含む部材である。このように、基板３は、それぞれ材質の異なるガラス基材３ａと流路構成部材３ｂから構成したが、基材と流路構成部材とを同じ材料としてもよいことは言うまでもない。なお、図１においては、構成の明瞭化のため、基材と流路構成部材とを同一の部材である基板として説明した。   First, a plate-like glass substrate 3a is prepared. Next, as shown in FIG. 4A, the optical fiber 7 (see FIG. 3) is fixed to a predetermined position on the upper surface of the glass substrate 3a with an adhesive or the like. Further, a flow path constituting member 3b that covers the optical fiber 7 and constitutes the flow path wall of the flow path is laminated on the upper surface of the glass substrate 3a with a predetermined thickness. The material of the flow path component 3b is a member containing a photosensitizer mainly composed of PMMA (poly (methylmethacrylate)), PDMS (poly (dimethylsiloxane)), polycarbonate, resists, and the like. is there. Thus, although the board | substrate 3 comprised the glass base material 3a and the flow-path structural member 3b from which material differs, respectively, it cannot be overemphasized that a base material and a flow-path structural member are good also as the same material. In FIG. 1, the base material and the flow path constituting member have been described as substrates that are the same member in order to clarify the configuration.

次に、流路構成部材が感光性材料から形成されている場合、流路パターンが形成されたマスク３７を介して、流路構成部材３ｂに紫外線を照射し露光を行う（図３（ｃ）参照）。次は、露光された部分（ポジ型）または露光されなかった部分（ネガ型）を現像除去することにより流路５が形成される。もちろん、第１実施形態同様にポジ型の光感応性樹脂を用いてもよいことは言うでもない。なお、流路構成部材に感光性材料を用いない場合には、流路パターンを有する鋳型に樹脂材料を流し込み、樹脂材料を固化させた後、鋳型より引き剥がして流路を有する流路構成部材を得る。   Next, when the flow path component is made of a photosensitive material, exposure is performed by irradiating the flow path component 3b with ultraviolet rays through the mask 37 on which the flow path pattern is formed (FIG. 3C). reference). Next, the flow path 5 is formed by developing and removing the exposed part (positive type) or the unexposed part (negative type). Of course, it goes without saying that a positive photosensitive resin may be used as in the first embodiment. In the case where a photosensitive material is not used for the flow path component member, the resin material is poured into a mold having a flow path pattern, the resin material is solidified, and then peeled off from the mold to have a flow path structure member. Get.

上記構成の流路形成チップの使用方法について説明する。流路５、生体試料導入路３９の全体に緩衝液を満たす。その後、生体試料導入路３９の両端に電圧を印加し、生体試料導入路３９の一端から生体試料であるＤＮＡを導入すると、ＤＮＡで生体試料導入路が均一にみたされる。次に、印加電圧を切り替え、流路５に電圧をかけると、流路５と試料導入路３９の交差部に存在する一定量のＤＮＡが流路５へと移送される。   A method of using the flow path forming chip having the above configuration will be described. The entire flow path 5 and biological sample introduction path 39 are filled with a buffer solution. Thereafter, when a voltage is applied to both ends of the biological sample introduction path 39 and DNA, which is a biological sample, is introduced from one end of the biological sample introduction path 39, the biological sample introduction path is uniformly seen with the DNA. Next, when the applied voltage is switched and a voltage is applied to the flow path 5, a certain amount of DNA present at the intersection of the flow path 5 and the sample introduction path 39 is transferred to the flow path 5.

その一定量のＤＮＡが流路５内を移動し、光ファイバ７のキャップ３３の近傍を通過する際、光源９からのパルス状の励起光５１を照射する。励起光５１に励起された蛍光体２７が発した放射光５３は、ビームスプリッタ２９、フィルタ３５を経由して測温部１９に到達する。そして、測温部１９により、ＤＮＡの温度が算出される。   When the certain amount of DNA moves in the flow path 5 and passes near the cap 33 of the optical fiber 7, the pulsed excitation light 51 from the light source 9 is irradiated. Radiated light 53 emitted from the phosphor 27 excited by the excitation light 51 reaches the temperature measuring unit 19 via the beam splitter 29 and the filter 35. Then, the temperature measuring unit 19 calculates the temperature of the DNA.

このように、電界によって生体試料を移動させる場合のように、高電圧、高周波が負荷される環境であっても、生体試料の測温を高精度でかつ簡易な構成において行うことができる。   As described above, even in an environment where a high voltage and a high frequency are loaded as in the case of moving a biological sample by an electric field, temperature measurement of the biological sample can be performed with high accuracy and a simple configuration.

なお、上記説明において、測温対象物はDNAであるが、RNA、タンパク質、ミトコンドリア等の細胞内器官、単一の細胞等でも本発明の蛍光式温度測定部材を有する流路形成チップを利用できることは言うまでもない。   In the above description, the temperature measuring object is DNA, but the flow path forming chip having the fluorescent temperature measuring member of the present invention can be used for intracellular organs such as RNA, protein, mitochondria, single cells, etc. Needless to say.

上記実施形態では、単一の蛍光式光ファイバを流路形成チップに設ける構成としたが、本発明はこの構成に限定されるものではない。例えば、流路５に沿って、光ファイバを複数設置する構成とすることができる。この構成によれば、流路内を移動する生体試料の温度分布を検出することが可能となる。   In the above embodiment, a single fluorescent optical fiber is provided in the flow path forming chip. However, the present invention is not limited to this configuration. For example, a plurality of optical fibers can be installed along the flow path 5. According to this configuration, it is possible to detect the temperature distribution of the biological sample moving in the flow path.

（実施形態２）
本発明の蛍光式温度測定部材を備える流路形成チップの第２の実施形態について図５、６を参照しつつ説明する。本実施形態の流路形成チップは、生体試料中の所定の検出物を捕集するために使用される例である。図５は、流路形成チップ１０１の平面図である。図６は、図５の線ＶＩ−ＶＩに沿った流路形成チップの断面図である。図７は、検出部の拡大図である。 (Embodiment 2)
A second embodiment of the flow path forming chip provided with the fluorescent temperature measuring member of the present invention will be described with reference to FIGS. The flow channel forming chip of the present embodiment is an example used for collecting a predetermined detection object in a biological sample. FIG. 5 is a plan view of the flow path forming chip 101. FIG. 6 is a cross-sectional view of the flow path forming chip taken along line VI-VI in FIG. FIG. 7 is an enlarged view of the detection unit.

流路形成チップ１０１は、略矩形状の板状部材であり、ガラス製の基材１１１の表面に、膜状電極１１６が積層され、さらに、膜状電極１１６の上に光感応性樹脂層１１２が積層される。   The flow path forming chip 101 is a substantially rectangular plate-like member, and a film electrode 116 is laminated on the surface of a glass substrate 111, and the photosensitive resin layer 112 is further formed on the film electrode 116. Are stacked.

膜状電極１１６は、外部電極に接続され、流路形成チップ１０１に投入される生体試料を移動させるため電界が形成される。なお、図５中において、膜状電極１１６がハッチングで示されている。また、破線のハッチングは、光感応性樹脂層１１２の下側に延在することを示し、実線のハッチングは、露出していることを示す。   The membrane electrode 116 is connected to an external electrode, and an electric field is formed to move the biological sample put into the flow path forming chip 101. In FIG. 5, the membrane electrode 116 is indicated by hatching. Moreover, the broken-line hatching indicates that it extends below the photosensitive resin layer 112, and the solid-line hatching indicates that it is exposed.

本実施形態では、膜状電極１１６として、上側にＰｔを、下側にＴｉを配置する２層構造とした。Tｉにより、基材１１１との密着性を向上させることができ、Pｔを用いることで、生体試料が接触することによる電解腐食を防止するためである。   In this embodiment, the film electrode 116 has a two-layer structure in which Pt is disposed on the upper side and Ti is disposed on the lower side. This is because the adhesion with the substrate 111 can be improved by Ti, and by using Pt, electrolytic corrosion due to contact of the biological sample is prevented.

なお、膜状電極１１６の露出する表面については、Ａｕ、Ａｇ等の相対的に標準電極電位が高い材料とすることが電解腐食の観点から望ましい。
光感応性樹脂層１１２の表面には、流路パターンを有するマスクを介して紫外光を照射し、現像液で未硬化部分を溶解、除去すること（ネガ型）で、所定深さの凹溝１０２が形成される。なお、凹溝１０２は、４つであり、それぞれ同一形状、同一寸法である。 The exposed surface of the film electrode 116 is preferably made of a material having a relatively high standard electrode potential such as Au or Ag from the viewpoint of electrolytic corrosion.
The surface of the photosensitive resin layer 112 is irradiated with ultraviolet light through a mask having a flow path pattern, and uncured portions are dissolved and removed with a developer (negative type), thereby forming a groove having a predetermined depth. 102 is formed. There are four concave grooves 102, each having the same shape and the same dimensions.

凹溝１０２は、生体試料投入槽１３１、廃液槽１３２、及び流路１０５から構成されている。また、凹溝１０２は、図５において上下対称である。すなわち、一対の略三角形状の溝を連結した形状である。図中において上側の略三角形状の部分が、試料投入槽１３１となり、連結部が流路１０５となる。また、流路１０５の延在方向のほぼ中央部には、検出部１３４が形成されている。   The concave groove 102 includes a biological sample charging tank 131, a waste liquid tank 132, and a flow path 105. Further, the concave groove 102 is vertically symmetric in FIG. That is, it is a shape in which a pair of substantially triangular grooves are connected. In the drawing, a substantially triangular portion on the upper side is a sample charging tank 131 and a connecting portion is a flow path 105. In addition, a detection unit 134 is formed at a substantially central portion in the extending direction of the flow path 105.

試料投入槽１３１及び廃液槽１３２は、生体試料を投入又は回収するためのものである。膜状電極１１６が試料投入槽１３１及び廃液槽１３２に延在し、それぞれ外部からの陽極または陰極が接続されている。よって、陽極電極に電圧を印加すると、電気浸透流が発生し、流路１０５内を、生体試料が試料投入槽１３１から廃液槽１３２、もしくは廃液槽１３２から試料投入槽１３１へと流れる。   The sample loading tank 131 and the waste liquid tank 132 are for loading or collecting a biological sample. A film electrode 116 extends to the sample charging tank 131 and the waste liquid tank 132, and an anode or a cathode from the outside is connected to each. Therefore, when a voltage is applied to the anode electrode, an electroosmotic flow is generated, and the biological sample flows in the flow path 105 from the sample charging tank 131 to the waste liquid tank 132 or from the waste liquid tank 132 to the sample charging tank 131.

流路１０５のほぼ中央部には、検出部１３４及び検出媒体であるシリカビーズ１３５が配置されている。流路幅及び流路深さは、生体試料に含まれる検出対象物質及びシリカビーズ１３５が通過できるようにシリカビーズの直径より大きく寸法付けられ、検出部１３４の流路幅及び流路深さはシリカビーズ１３５の直径より小さく寸法付けられている。よって、シリカビーズ１３５は、検出部１３４に引っ掛かる構成である。なお、流路１０５の、検出部１３４を除いた部分においても、シリカビーズが２個同時に通過できないように寸法づけされている。   A detection part 134 and silica beads 135 as a detection medium are arranged at a substantially central part of the flow path 105. The channel width and the channel depth are dimensioned larger than the diameter of the silica beads so that the detection target substance and the silica beads 135 contained in the biological sample can pass, and the channel width and the channel depth of the detection unit 134 are It is dimensioned smaller than the diameter of the silica beads 135. Therefore, the silica beads 135 are configured to be caught by the detection unit 134. Note that the portion of the flow path 105 excluding the detection unit 134 is dimensioned so that two silica beads cannot pass simultaneously.

シリカビーズ１３５は、例えばＳｉＯ２（シリカ）を主成分とする材料からなり、その表面に無数の細孔が設けられた球形状である。このシリカビーズ１３５の細孔に目的とする分子を吸着する。さらに、検出対象物を特定するために、タンパク分子等に反応する酵素等をプローブとして細孔に装着してもよい。 The silica beads 135 are made of, for example, a material mainly composed of SiO 2 (silica), and have a spherical shape with innumerable pores provided on the surface thereof. The target molecules are adsorbed in the pores of the silica beads 135. Furthermore, in order to specify the detection target, an enzyme that reacts with a protein molecule or the like may be attached to the pore as a probe.

さらに、図３に示した光ファイバ７と同様の光ファイバ１０７の一端部が各検出部１３４の近傍で流路１０５に面して配置されている。なお、各流路１０５には、それぞれ光ファイバ１０７が設けられている。また、光ファイバ１０７の他端部は、流路形成チップ１０１の外部で蛍光式温度測定部材１１３の本体部１１４に連結されている。本体部１１４は、図２に示した構成と同様の、光検出部、温度検出部、光源、ビームスピリッタ、フィルタを備えている。   Furthermore, one end portion of the optical fiber 107 similar to the optical fiber 7 shown in FIG. 3 is arranged facing the flow path 105 in the vicinity of each detection unit 134. Each flow path 105 is provided with an optical fiber 107. The other end of the optical fiber 107 is connected to the main body 114 of the fluorescent temperature measuring member 113 outside the flow path forming chip 101. The main body 114 includes a light detection unit, a temperature detection unit, a light source, a beam spiriter, and a filter similar to the configuration shown in FIG.

上記構成の蛍光式温度測定部材１１３を備える流路形成チップ１０１の動作は以下のようになされる。例えばＤＮＡ断片を試料投入槽１３１に投入する。膜状電極１１６の試料投入槽１３１側を陽極、廃液槽１３２側を陰極とし電圧を印加すると、試料投入槽１３１側から廃液槽１３２側への電気浸透流が形成される。ＤＮＡ断片が試料投入槽１３１から廃液槽１３２方向へ移動する。ＤＮＡ断片は検出部１３４を通過する際に所定のＤＮＡがシリカビーズ１３５に吸着される。   The operation of the flow path forming chip 101 including the fluorescent temperature measuring member 113 having the above-described configuration is performed as follows. For example, the DNA fragment is loaded into the sample loading tank 131. When a voltage is applied using the membrane electrode 116 as an anode and the waste liquid tank 132 as a cathode, an electroosmotic flow from the sample tank 131 to the waste liquid 132 is formed. The DNA fragment moves from the sample charging tank 131 toward the waste liquid tank 132. When the DNA fragment passes through the detection unit 134, predetermined DNA is adsorbed on the silica beads 135.

上記検出作業の温度管理は、以下のように行われ、光ファイバ１０７を介して光源から励起光を照射し、蛍光体に到達する。そして蛍光式温度測定部材１１３の本体１１４において蛍光体からの放射光の光強度の減衰曲線を検出して検出部１３４近傍の温度を計測することができる。このように、温度測定は、実施形態１の構成と同様の方法で行われ、検出作業における温度管理を高精度で行うことができる。   The temperature management of the detection operation is performed as follows, and the excitation light is irradiated from the light source via the optical fiber 107 to reach the phosphor. Then, the temperature in the vicinity of the detection unit 134 can be measured by detecting the attenuation curve of the light intensity of the radiated light from the phosphor in the main body 114 of the fluorescent temperature measuring member 113. As described above, the temperature measurement is performed by the same method as the configuration of the first embodiment, and the temperature management in the detection work can be performed with high accuracy.

なお、電気浸透流の流れ方向を廃液槽１３２側から試料投入槽１３１側へとしてもよいことは言うまでもない。但し、その場合には、シリカビーズを検出部において廃液槽側で引っ掛かるように配置することが必要である。
蛍光式光ファイバを各流路に一つづつ配置したが、流路に沿って複数配置したり、試料投入槽や廃液槽に設けてもよいことは言うまでもない。 Needless to say, the flow direction of the electroosmotic flow may be changed from the waste liquid tank 132 side to the sample charging tank 131 side. However, in that case, it is necessary to dispose the silica beads so as to be caught on the waste liquid tank side in the detection unit.
Although one fluorescent optical fiber is disposed in each flow path, it goes without saying that a plurality of fluorescent optical fibers may be disposed along the flow path, or may be provided in a sample charging tank or a waste liquid tank.

上記実施形態１、２では、表面に流路が露出した流路形成チップを用いたが、薄板状の部材を流路形成チップの流路が形成されている表面に貼付し、薄板状の部材に、生体試料を投入するための流路に連通する穴を設けた構成の部材としてもよいことは言うまでもない。   In the first and second embodiments, the flow path forming chip with the flow path exposed on the surface is used. However, a thin plate member is attached to the surface of the flow path forming chip where the flow path is formed, and the thin plate shaped member is used. Needless to say, a member having a hole communicating with the flow path for introducing the biological sample may be used.

なお、上記実施形態１、２の流路形成チップにおいて、電気浸透流を用いて生体試料を流路で移動させる構成としたが、流路の両端に電圧をかけて、負電荷を帯びている生体試料を移動させる構成であってもよい。   In the flow path forming chip of the first and second embodiments, the biological sample is moved in the flow path using electroosmotic flow. However, a voltage is applied to both ends of the flow path to carry negative charges. The structure which moves a biological sample may be sufficient.

この発明は、その本質的特性から逸脱することなく数多くの形式のものとして具体化することができる。よって、上述した実施形態は専ら説明上のものであり、本発明を制限するものではないことは言うまでもない。   The present invention can be embodied in many forms without departing from its essential characteristics. Therefore, it is needless to say that the above-described embodiment is exclusively for description and does not limit the present invention.

流路形成チップの斜視図である。It is a perspective view of a channel formation chip. （ａ）の流路形成チップの平面図である。It is a top view of the flow-path formation chip | tip of (a). 蛍光性温度測定部材の構成図である。It is a block diagram of a fluorescent temperature measuring member. （ａ）〜（ｃ）は、光ファイバを形成する工程を示す横断面図である。(A)-(c) is a cross-sectional view which shows the process of forming an optical fiber. （ａ）〜（ｄ）は、流路形成チップを作製する工程を示す横断面図である。(A)-(d) is a cross-sectional view which shows the process of producing a flow-path formation chip | tip. 実施形態２に係る流路形成チップの平面図である。6 is a plan view of a flow path forming chip according to Embodiment 2. FIG. 図５の線ＶＩ−ＶＩに沿った流路形成チップの縦方向断面図である。FIG. 6 is a longitudinal sectional view of the flow path forming chip along line VI-VI in FIG. 5. 検出部の拡大図である。It is an enlarged view of a detection part.

符号の説明Explanation of symbols

１ 生体試料用の流路形成チップ
３ 基板
５ 流路
７ 光ファイバ
９ 光源
１３ 蛍光式温度測定手段
１４ 測温装置本体
１５ 光検出部
１７ 温度検出部
２３ ＣＣＤカメラ
２５ 生体試料
２７ 蛍光体
３１ 反射膜 DESCRIPTION OF SYMBOLS 1 Flow path formation chip | tip for biological samples 3 Substrate 5 Flow path 7 Optical fiber 9 Light source 13 Fluorescence type temperature measurement means 14 Temperature measuring device main body 15 Light detection part 17 Temperature detection part 23 CCD camera 25 Biological sample 27 Phosphor 31 Reflective film

Claims (10)

生体試料用の流路形成チップであって、
生体試料を流動させるための流路が表面に設けられた板状の基板と、
前記流路内の前記生体試料に接触可能な反射膜と、前記反射膜に装着された蛍光体と、前記蛍光体に励起光を照射する光源と、前記励起光による前記蛍光体の発光強度の減衰特性から前記生体試料の温度を測定する測温部と、前記蛍光体に前記光源及び前記測温部を連結する光ファイバと、を有する蛍光式温度測定部材と、を備え、
前記蛍光体は、前記光ファイバの端部と前記反射膜との間に介在している流路形成チップ。 A flow path forming chip for a biological sample,
A plate-like substrate provided on the surface with a flow path for flowing a biological sample;
A reflective film that can contact the biological sample in the flow path; a phosphor mounted on the reflective film; a light source that irradiates the phosphor with excitation light; and an emission intensity of the phosphor by the excitation light. A temperature measuring unit that measures the temperature of the biological sample from attenuation characteristics, and a fluorescent temperature measuring member that includes an optical fiber that connects the light source and the temperature measuring unit to the phosphor, and
The phosphor is a flow path forming chip interposed between an end of the optical fiber and the reflective film. 反射膜は、熱伝導体である請求項１に記載の生体試料用の流路形成チップ。   The flow path forming chip for a biological sample according to claim 1, wherein the reflective film is a heat conductor. 前記反射膜は、反射率が相対的に高い、金属膜もしくは誘電体多層膜である請求項１又は２に記載の生体試料用の流路形成チップ。   The flow path forming chip for a biological sample according to claim 1 or 2, wherein the reflective film is a metal film or a dielectric multilayer film having a relatively high reflectance. 前記蛍光式温度測定部材が、複数配置されている請求項１〜３のいずれか一項に記載の生体試料用の流路形成チップ。   The flow path forming chip for a biological sample according to any one of claims 1 to 3, wherein a plurality of the fluorescent temperature measuring members are arranged. 前記光ファイバの一端部には、前記反射膜および前記蛍光体を覆うようにキャップが装着されている請求項１〜４のいずれか一項に記載の生体試料用の流路形成チップ。   The flow path forming chip for a biological sample according to any one of claims 1 to 4, wherein a cap is attached to one end of the optical fiber so as to cover the reflective film and the phosphor. 前記流路の一端部と他端部それぞれに、前記生体試料を流動させるための電極が形成されている請求項１〜５のいずれか一項に記載の生体試料用の流路形成チップ。   The flow channel forming chip for a biological sample according to any one of claims 1 to 5, wherein an electrode for allowing the biological sample to flow is formed in each of one end and the other end of the flow channel. さらに、前記流路内で移動可能に配された検出媒体を備え、前記流路の途中には、前記検出媒体の移動を拘束する検出部が設けられている請求項１〜６のいずれか一項に記載の生体試料用の流路形成チップ。   Furthermore, it has the detection medium arrange | positioned so that a movement in the said flow path is possible, The detection part which restrains the movement of the said detection medium is provided in the middle of the said flow path. A flow path forming chip for a biological sample according to Item. 生体試料用の流路形成チップの製造方法であって、
板状の基材と、蛍光式温度測定部材に連結可能な光ファイバと、を用意し、
前記基板の表面の所定位置に前記光ファイバを固定し、
前記基板の前記光ファイバが固定された面に光感応性樹脂を積層し、
所定の流路パターンを有するマスクを介して前記光感応性樹脂に紫外線を照射し、
前記光感応性樹脂を現像し、前記所定の流路パターンを有する流路を形成し、
前記光ファイバの一端部は、前記流路を移動する前記生体試料に接するように前記流路に面するように配置される流路形成チップの製造方法。 A method of manufacturing a flow path forming chip for a biological sample,
Prepare a plate-like substrate and an optical fiber that can be connected to a fluorescent temperature measuring member,
Fixing the optical fiber at a predetermined position on the surface of the substrate;
Laminating a photosensitive resin on the surface of the substrate on which the optical fiber is fixed,
Irradiating the photosensitive resin with ultraviolet rays through a mask having a predetermined flow path pattern,
Developing the photosensitive resin to form a flow path having the predetermined flow path pattern;
The manufacturing method of the flow-path formation chip | tip arrange | positioned so that the one end part of the said optical fiber may face the said flow path so that the said biological sample which moves the said flow path may be contact | connected. 前記光感応性樹脂はポジ型又はネガ型である請求項８に記載の流路形成チップの製造方法。   The method for manufacturing a flow path forming chip according to claim 8, wherein the photosensitive resin is a positive type or a negative type. 前記基板に固定される前記光ファイバは複数である請求項８又は９に記載の流路形成チップの製造方法。   The method of manufacturing a flow path forming chip according to claim 8 or 9, wherein a plurality of the optical fibers are fixed to the substrate.
JP2007034987A 2007-02-15 2007-02-15 Flow-channel formation chip for biological sample, and manufacturing method for the flow-channel formation chip for biological sample Pending JP2008197053A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010081898A (en) * 2008-10-01 2010-04-15 Canon Inc System for gene test
JP2011513743A (en) * 2008-03-03 2011-04-28 ロディア オペレーションズ Method and apparatus for determining at least one parameter of physical and / or chemical transition

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011513743A (en) * 2008-03-03 2011-04-28 ロディア オペレーションズ Method and apparatus for determining at least one parameter of physical and / or chemical transition
JP2010081898A (en) * 2008-10-01 2010-04-15 Canon Inc System for gene test

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